The Yale Medications Development Research Center (YMDRC) will continue the interdisciplinary research of our Treatment Research Unit (TRU) on the efficacy of treatments for opioid and cocaine dependence. During the four years of our TRU we have treated over 700 patients in clinical research including multisite NIDA trials. In our YMDRC we expect to enroll 350 inpatients and 600 outpatients. Our research theme will be a planned development of treatments for cocaine and opioid abuse. Potential new treatment strategies are drawn from relevant preclinical and clinical research, refined in inpatient human experimental studies, and subjected to randomized outpatient clinical trials. The inpatient studies include pharmacokinetic profiling and performance testing of investigational agents such as high dose maxindol (6-12 mb/day) and the atypical antipsychotic clozapine for cocaine abuse, and butyric acid and caramifen for opioid dependence. Buprenorphine will be examined pharmacokinetically to assess its opioid blockade duration and withdrawal syndrome. Pharmacological challenges with dopaminergic and serotonergic agents as well as with cocaine will be used to predict pharmacotherapeutic response in subsequent outpatient trials. Calcium channel and excitatory amino acid antagonists will be examined for their capacities to block cocaine effects. Six month outpatient randomized clinical trials will evaluate the efficacy and safety of investigational approaches such as maxindol for cocaine abuse in cocaine abusers with concurrent major psychiatric disorders or on methadone maintenance. LAAM will be examined in conjunction with behavioral contingencies for the cocaine abusing opiate addict. Outpatient studies will be tied to cost efficacy analyses using six and twelve month follow-up data.